US10926031B2 - Hierarchical adaptive closed-loop fluid resuscitation and cardiovascular drug administration system - Google Patents

Hierarchical adaptive closed-loop fluid resuscitation and cardiovascular drug administration system Download PDF

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US10926031B2
US10926031B2 US16/680,145 US201916680145A US10926031B2 US 10926031 B2 US10926031 B2 US 10926031B2 US 201916680145 A US201916680145 A US 201916680145A US 10926031 B2 US10926031 B2 US 10926031B2
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infusion rate
level controller
user
infusion
controller
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US20200114077A1 (en
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Behnood Gholami
Timothy S. Phan
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Autonomous Healthcare Inc
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Autonomous Healthcare Inc
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Definitions

  • the invention was made with government support under W81XWH-14-C-1385 by the US Army Medical Research and Material Command, under IIP-1648292 by the National Science Foundation, and under IIP-1831225 by the National Science Foundation. The government has certain rights in the invention.
  • Fluid resuscitation i.e., intravenous administration of fluids
  • ICU intensive care unit
  • the goal of fluid resuscitation is to restore blood volume in the circulatory system to an acceptable level to ensure adequate tissue perfusion.
  • large intra-patient and inter-patient variability in physiological parameters, and the effects of different illnesses and medications can result in under-resuscitation and over-resuscitation of patients.
  • the disclosure provides a method for fluid resuscitation and/or cardiovascular drug administration comprising: a) initiating an infusion rate of a fluid and/or a cardiovascular drug into a subject at an infusion rate; b) receiving hemodynamic sensor data of the subject from at least one medical monitoring device attached to the subject by a hierarchical control architecture system, wherein the hierarchical control architecture system comprises: at least one adaptive controller; and a logic-based controller; wherein the subject's hemodynamic data is received by the logic-based controller and the at least one adaptive controller, wherein the at least one adaptive controller and the logic-based controller are in communication with one another; c) generating by the at least one adaptive controller an altered infusion rate based on the subject's hemodynamic data, previous infusion rates, and internal parameters and states of the at least one adaptive controller; d) verifying by the logic-based controller that the subject's hemodynamic data and the at least one adaptive controller states do not violate rules governing the operation of the at least one adaptive controller; e) sending the altered
  • the disclosure provides a method for fluid resuscitation and/or cardiovascular drug administration clinical decision support comprising: a) asking a user to provide an initial infusion rate of a fluid and/or a cardiovascular drug; b) receiving hemodynamic sensor data of the subject from at least one medical monitoring device attached to the subject by a hierarchical control architecture system, wherein the hierarchical control architecture system comprises: at least one adaptive controller; and a logic-based controller; wherein the subject's hemodynamic data is received by the logic-based controller and the at least one adaptive controller, wherein the at least one adaptive controller and the logic-based controller are in communication with one another; c) generating by the at least one adaptive controller an altered infusion rate based on the subject's hemodynamic data, previous infusion rates, and internal parameters and states of the at least one adaptive controller; d) verifying by the logic-based controller that the hemodynamic data and the at least one adaptive controller states do not violate rules governing the operation of the at least one adaptive controller; e) verifying by the logic-based
  • this disclosure provides for a clinical decision support (semi-automated) system for notifying a user through audio-visual alarms if certain infusion therapy performance criteria are violated.
  • a notification can be issued by a higher-level logic-based controller.
  • the notification asks the user to change the therapy type from one type to another. For example, in some embodiments, if the subject was being administered with fluid, the user can be asked to consider administering a vasopressor.
  • this disclosure provides for a clinical decision support system for issuing a prompt when a change in infusion therapy is implicated based at least on a background infusion rate.
  • An appropriate notification message and/or an appropriate change in infusion therapy recommendation message may be determined. Further, the appropriate notification message and/or the appropriate recommendation message may be displayed.
  • this disclosure provides for an apparatus for displaying infusion therapy information which can be used to optimize infusion therapy.
  • the apparatus comprises a memory, a display, and a processor in operable communication with the memory and the display.
  • the display displays at least one appropriate notification message and appropriate change in infusion therapy recommendation when the processor issues the notification message and/or the recommendation message upon implication for a change in infusion therapy based at least on an active infusion rate stored in memory and a background infusion rate.
  • the background infusion rate is calculated by a lower-level controller based at least on received sensor measurement from a hemodynamic monitoring device.
  • FIG. 1A is a diagram that illustrates a two-compartment model of fluid exchange in the body for non-burn patients.
  • FIG. 1B is a diagram that illustrates a three-compartment model of the microvascular exchange system for burn patients.
  • FIG. 1C is a diagram that illustrates a two-compartment model of cardiovascular drug exchange in the body.
  • FIG. 2A is a diagram that illustrates the overall architecture of a fully automated closed-loop fluid resuscitation or cardiovascular drug administration system.
  • FIG. 2B is a diagram that illustrates the overall architecture of a fully automated closed-loop fluid resuscitation and cardiovascular drug administration system.
  • FIG. 3A is a diagram that illustrates the overall architecture of a partially automated (clinical decision support) fluid resuscitation or cardiovascular drug administration system.
  • FIG. 3B is a diagram that illustrates the overall architecture of a partially automated (clinical decision support) fluid resuscitation and cardiovascular drug administration system.
  • FIG. 4A is a diagram that illustrates components of a fully automated, closed-loop fluid resuscitation or cardiovascular drug administration system.
  • FIG. 4B is a diagram that illustrates components of a fully automated, closed-loop fluid resuscitation and cardiovascular drug administration system.
  • FIG. 5A is a diagram that illustrates components of a partially automated clinical decision support fluid resuscitation or cardiovascular drug administration system.
  • FIG. 5B is a diagram that illustrates components of a partially automated clinical decision support fluid resuscitation and cardiovascular drug administration system.
  • FIG. 6 is a flow chart that illustrates the lower-level adaptive control architecture according to embodiments.
  • FIG. 7 is a graph that depicts exemplary stroke volume variation versus time.
  • FIG. 8 is a graph that depicts exemplary fluid infusion rates computed by the adaptive control framework.
  • FIG. 9 is a graph that depicts exemplary plasma volume in circulation versus time.
  • FIG. 10 is a graph that depicts exemplary changes in filtered SVV (%) in 2 canine subjects experiencing controlled hemorrhage.
  • FIG. 11 is a graph that depicts exemplary changes in infusion rates in 2 canine subjects experiencing controlled hemorrhage.
  • FIG. 12 is a graph that depicts exemplary changes in filtered SVV (%) in 3 canine subjects experiencing uncontrolled hemorrhage.
  • FIG. 13 is a graph that depicts exemplary changes in infusion rates in 3 canine subjects experiencing uncontrolled hemorrhage.
  • FIG. 14 is a graph that depicts exemplary changes in filtered SVV (%) in 2 canine subjects that were hypotensive as a result of administration of sodium nitroprusside (S4-1) and increase in isoflurane (S5-1).
  • FIG. 15 is a graph that depicts exemplary changes in infusion rates in 2 canine subjects that were hypotensive as a result of administration of sodium nitroprusside (S4-1) and increase in isoflurane (S5-1).
  • FIG. 16 is a flow chart that illustrates components of the higher-level controller for the closed-loop fluid resuscitation system in embodiments.
  • FIG. 17 is a flow chart that illustrates components of the higher-level controller for the clinical decision support case in embodiments.
  • FIG. 18 is a graph that depicts exemplary mean arterial pressure versus time.
  • FIG. 19 is a graph that depicts exemplary cardiovascular drug infusion rates computed by the adaptive control framework.
  • FIG. 20 is a graph that depicts exemplary mean arterial pressure versus time.
  • FIG. 21 is a graph that depicts exemplary fluid infusion rates computed by the adaptive control framework.
  • FIG. 22 is a graph that depicts exemplary stroke volume variation versus time.
  • FIG. 23 is a graph that depicts exemplary fluid infusion rates computed by the fluid resuscitation adaptive control framework.
  • FIG. 24 is a graph that depicts exemplary mean arterial pressure versus time.
  • FIG. 25 is a graph that depicts exemplary vasopressor infusion rates computed by the cardiovascular drug administration adaptive control framework.
  • FIG. 26 is a diagram that depicts an embodiment of a fluid resuscitation and cardiovascular drug administration system implemented on hardware.
  • FIG. 27 is a block diagram illustrating an embodiment of the apparatus for displaying infusion therapy information for optimizing infusion therapy.
  • FIG. 28 is a diagram that depicts an embodiment of the apparatus for displaying infusion therapy information for optimizing infusion therapy.
  • FIG. 29 is a flow chart that illustrates the administration of pre-approved ranges of infusion rates according to embodiments.
  • FIG. 30 is a flow chart that illustrates the alarm function to prevent under- or over-administration of fluid and/or drug according to embodiments.
  • Fluid management is required for surgical patients as well as patients suffering from hypovolemia, sepsis, severe sepsis, septic shock, burn, and other conditions.
  • the goal of fluid resuscitation is to restore blood volume in the circulatory system to an acceptable level in order to ensure adequate tissue perfusion (i.e., blood delivery to tissue).
  • tissue perfusion i.e., blood delivery to tissue.
  • Cardiovascular drug administration can be used independently to address a clinical condition (e.g., vasopressors are used to increase blood pressure to a clinically acceptable value or inotropic agents are used to change the contractility of the heart). Cardiovascular drugs, such as vasopressors, are administered independent of fluids in critical care for hypotensive patients. Cardiovascular drugs can also be used in combination with fluid resuscitation. For example, to address hypotension and hypovolemia in sepsis and during surgery, a vasopressor and fluid can be administered simultaneously.
  • a vasopressor and fluid can be administered simultaneously.
  • the present disclosure describes a reliable and consistent closed-loop fluid resuscitation system, a clinical decision support fluid resuscitation system, a closed-loop cardiovascular drug administration system, a clinical decision support cardiovascular drug administration system, a closed-loop fluid and cardiovascular drug administration system, and a clinical decision support fluid and cardiovascular drug administration system.
  • the system uses continuous measurements from standard operating room (OR) or ICU hemodynamic monitoring devices or sensors or a built-in or add-on modules to measure such continuous measures to compute the required fluid and/or cardiovascular drug infusion rates for patients receiving continuous infusion.
  • Adaptive control architecture is used to compute the required infusion rates to regulate an endpoint of fluid or drug administration including, but not limited to, static indicators of fluid responsiveness and dynamic indicators of fluid responsiveness for the fluid resuscitation module, and hemodynamic measures for the cardiovascular drug administration module.
  • the static indicators of fluid responsiveness include mean arterial pressure, central venous pressure, heart rates, cardiac output, stroke volume, cardiac index, and urine output rates of patients.
  • dynamic indicators of fluid responsiveness include stroke volume variation, pulse pressure variations, systolic pressure variation, dynamic arterial elastance, and pleth variability indices of patients.
  • hemodynamic measures include mean arterial pressure, central venous pressure, systolic pressure, diastolic pressure, heart rate, cardiac output, cardiac index, systemic vascular resistance, stroke volume, and urine output.
  • the closed-loop fluid resuscitation and/or cardiovascular drug administration system described herein comprises an adaptive controller or two adaptive controllers that use a function approximator, such as a neural network, Fourier functions, or wavelets, to identify the unknown dynamics and physiological parameters of a patient to compute appropriate infusion rates and to regulate the endpoint of fluid resuscitation or cardiovascular drug administration.
  • the developed fluid resuscitation system can use either crystalloids or colloids during resuscitation and use vasoactive cardiovascular drugs (e.g., vasopressor) or inotropic agents.
  • the fluid infusion rate (e.g., in mL/hour) is highly dependent on a patient needs. In some embodiments, the fluid infusion rate can range from 0 to 3,000 mL/hr or more in humans, and 0 to 40,000 mL/h or more in animals.
  • the cardiovascular drug infusion rate (e.g., in mcg/kg/min) is highly dependent on a patient's needs.
  • the cardiovascular drug infusion rate (e.g., vasopressor or inotropic agents) can range from 0 mcg/kg/min to 40 mcg/kg/min, or can exceed 40 mcg/kg/min.
  • Any method or algorithm described herein can be embodied in software or set of computer-executable instructions capable of being run on a computing device or devices.
  • the computing device or devices can include one or more processor (CPU) and a computer memory.
  • the computer memory can be or include a non-transitory computer storage media such as RAM which stores the set of computer-executable (also known herein as computer readable) instructions (software) for instructing the processor(s) to carry out any of the algorithms, methods, or routines described in this disclosure.
  • a non-transitory computer-readable medium can include any kind of computer memory, including magnetic storage media, optical storage media, nonvolatile memory storage media, and volatile memory.
  • Non-limiting examples of non-transitory computer-readable storage media include floppy disks, magnetic tape, conventional hard disks, CD-ROM, DVD-ROM, BLU-RAY, Flash ROM, memory cards, optical drives, solid state drives, flash drives, erasable programmable read only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), non-volatile ROM, and RAM.
  • the computer-readable instructions can be programmed in any suitable programming language, including JavaScript, C, C#, C++, Java, Python, Perl, Ruby, Swift, Visual Basic, and Objective C.
  • Embodiments of the invention also include a non-transitory computer readable storage medium having any of the computer-executable instructions described herein.
  • firmware can include any software programmed onto the computing device, such as a device's nonvolatile memory.
  • systems of the invention can also include, alternatively or in addition to the computer-executable instructions, various firmware modules configured to perform the algorithms of the invention.
  • the computing device or devices can include a mainframe computer, web server, database server, desktop computer, laptop, tablet, netbook, notebook, personal digital assistant (PDA), gaming console, e-reader, smartphone, or smartwatch, which may include features such as a processor, memory, hard drive, graphics processing unit (GPU), and input/output devices such as display, keyboard, and mouse or trackpad (depending on the device).
  • PDA personal digital assistant
  • Embodiments can also provide a graphical user interface made available on one or more client computers. The graphical user interface can allow a user on a client computer remote access to the method or algorithm.
  • Additional embodiments of the invention can include a networked computer system for carrying out one or more methods of the invention.
  • the computer system can include one or more computing devices which can include a processor for executing computer-executable instructions, one or more databases, a user interface, and a set of instructions (e.g. software) for carrying out one or more methods of the invention.
  • the computing device or devices can be connected to a network through any suitable network protocol such as IP, TCP/IP, UDP, or ICMP, such as in a client-server configuration and one or more database servers.
  • the network can use any suitable network protocol and can be any suitable wired or wireless network including any local area network, wide area network, Internet network, telecommunications network, Wi-Fi enabled network, or Bluetooth enabled network.
  • the present disclosure models the microvascular exchange system to characterize the distribution of fluids in the body.
  • a two-compartment dynamic system model is used for all patient populations except for patients with burn injuries.
  • the compartments for two-compartment dynamic system models include circulation (blood) and interstitial tissue.
  • a 4th-order nonlinear state space model representation of the dynamic system can provide a simplified model of the microvascular exchange system for non-burn patients.
  • the states of the two-compartment dynamic system include the volume of fluids and albumin mass in each compartment (a total of four states).
  • a three-compartment model is used for patients with burn injuries.
  • the states of the three-compartment dynamic system model include circulation (blood), injured tissue, and uninjured tissue.
  • a 6th-order nonlinear state space model representation of the dynamic system can provide a simplified model of the microvascular exchange system for burn patients.
  • the states of the three-compartment dynamic system include volume of fluids and albumin mass in each compartment (a total of six states).
  • the parameters of the two- and three-compartment models of the microvascular exchange system characterize fluid and mass exchange between different compartments. These parameters are generally unknown and are different from patient to patient.
  • FIG. 1A illustrates a two-compartment model of the fluid exchange in the body for non-burn patients.
  • FIG. 1B illustrates a three-compartment model of the microvascular exchange system for burn patients.
  • a higher number of compartments are used to model the microvascular exchange system of a patient population.
  • a model dynamic system consists of 2, 3, 4, or 5 compartments.
  • a 1, 2, 3, or 4-compartment dynamic system model is used for a patient population.
  • a two-compartment dynamic system model is used for a patient population.
  • a three-compartment dynamic system model is used for a patient population.
  • a four-compartment dynamic system model is used for a patient population.
  • the present disclosure models the cardiovascular drug distribution in the body using a compartmental model.
  • Cardiovascular drug distribution can be modeled using a two-compartment model.
  • the compartments for two-compartment dynamic system models include circulation (blood) and tissue.
  • a 2nd-order nonlinear state space model representation of the dynamic system can provide a simplified model of the cardiovascular drug distribution for patients.
  • the states of the two-compartment dynamic system include the concentration of cardiovascular drug in each compartment.
  • FIG. 1C illustrates a two-compartment model of the cardiovascular drug distribution in the body.
  • a higher number of compartments are used to model the cardiovascular drug distribution for a patient.
  • a model dynamic system consists of 2, 3, 4, or 5 compartments.
  • a 1, 2, 3, or 4-compartment dynamic system model is used for a patient population.
  • a two-compartment dynamic system model is used for a patient population.
  • a three-compartment dynamic system model is used for a patient population.
  • a four-compartment dynamic system model is used for a patient population.
  • the disclosure provides an adaptive control architecture framework for a closed-loop fluid resuscitation and/or cardiovascular drug administration system.
  • the fluid resuscitation and/or cardiovascular drug administration system of the disclosure receives data from a monitoring system or a set of monitoring systems.
  • the fluid resuscitation and/or cardiovascular drug administration system receives data from an existing monitoring system or systems.
  • the fluid resuscitation and/or cardiovascular drug administration system receives data from a built-in monitoring system or systems.
  • the fluid resuscitation and/or cardiovascular drug administration system receives data from an add-on monitoring system or systems.
  • the received data comprises one of: blood pressure, heart rate, stroke volume variation, pulse pressure variation, dynamic arterial elastance, pleth variability index, urine output rate, systolic pressure variation, central venous pressure, mean arterial pressure, cardiac output, cardiac index, systolic pressure, diastolic pressure, systemic vascular resistance, or stroke volume.
  • the received data comprises a combination of blood pressure, heart rate, stroke volume variation, pulse pressure variation, dynamic arterial elastance, pleth variability index, urine output rate or urine output, systolic pressure variation, central venous pressure, mean arterial pressure, cardiac output, cardiac index, systolic pressure, diastolic pressure, systemic vascular resistance, or stroke volume.
  • a built-in or add-on monitoring system or systems are used and the input data includes one or a combination of an invasive blood pressure signal or a non-invasive pressure signal collected from a patient's arm or leg using a blood pressure cuff.
  • the disclosed fluid resuscitation and/or cardiovascular drug administration system can transmit data to a receiver or a set of receivers. In some embodiments, the disclosed fluid resuscitation and/or cardiovascular drug administration system can transmit data to an external or built-in infusion pump or infusion pumps, a user, an electronic medical record, or a remote location. In some embodiments, the disclosed fluid resuscitation and/or cardiovascular drug administration system can transmit data to a combination of receivers. In some embodiments, the disclosed fluid resuscitation and/or cardiovascular drug administration system can transmit data to an infusion pump or infusion pumps and a user or users. In some embodiments, the disclosed fluid resuscitation system can transmit data to an infusion pump or infusion pumps, a user or users, and an electric medical record. In some embodiments, the disclosed fluid resuscitation system can transmit data to an infusion pump or infusion pumps, a user or users, an electronic medical record, and a remote location.
  • the adaptive architecture of the disclosure can be implemented in a fully automated architecture or a partially automated architecture.
  • the adaptive architecture of the disclosure is implemented in a fully automated architecture, wherein the infusion rate of the infusion pump or infusion rates of the infusion pumps are updated automatically by the system using the most recent value of the infusion rate or infusion rates.
  • Partial automation also referred to as clinical decision support:
  • the adaptive architecture of the disclosure is implemented in a partially automated architecture.
  • the framework of the disclosure is used within a clinical decision support context, where recommended infusion rates are displayed to the end-user (clinician) for approval.
  • the system can request for approval before changing the infusion rate of the pump or pumps.
  • the end-user can use recommended infusion rate changes and manually change the infusion rate on the pump or pumps based on his/her clinical judgment and the recommendation provided by the clinical decision support system.
  • the end-user can enter whether the recommended infusion rate was accepted or rejected.
  • the end-user can enter a new manually changed infusion rate or infusion rates.
  • the system can automatically change the infusion rate of the pump or infusion rates of the pump after the user approves or modifies the recommended infusion rate or infusion rates.
  • the present disclosure is able to determine suitable infusion rates based on an input from patient-monitoring devices, built-in monitoring devices, add-on monitoring modules, or sensors. Infusion rates can be adjusted based on the input from patient-monitoring devices, built-in monitoring devices, add-on monitoring modules, or sensors.
  • the adaptive control framework of the disclosure does not require any patient-specific information (e.g., age, gender, weight, diagnosis). Furthermore, the framework does not require an accurate model of the patient dynamics and the patient-specific physiological parameters.
  • the present disclosure describes a closed-loop or clinical decision support fluid resuscitation and/or cardiovascular drug administration system predicated on hierarchical adaptive control architecture.
  • the hierarchical control architecture is composed of one or two lower-level adaptive controllers and a higher-level, logic-based controller.
  • the higher-level, logic-based controller is a rule-based expert system.
  • the hierarchical control architecture is composed of an adaptive controller fluid module and a higher-level, logic-based controller. If the system is used for only cardiovascular drug administration, the hierarchical control architecture is composed of an adaptive controller cardiovascular drug module and a higher-level, logic-based controller. If the system is used for fluid resuscitation and cardiovascular drug administration, the hierarchical control architecture is composed of an adaptive controller fluid module, an adaptive controller cardiovascular drug module, and a higher-level, logic-based controller.
  • the lower-level controller focused on fluid resuscitation uses an adaptive control framework to regulate a measure of fluid responsiveness to a desired value by adjusting the fluid infusion rate.
  • the lower-level controller can regulate mean arterial pressure, systolic pressure, diastolic pressure or a measure of fluid responsiveness including stroke volume variation, pleth variability index, pulse pressure variation, dynamic arterial elastance, central venous pressure, urine output rate or urine output, or systolic pressure variation. While the goal of this lower-level controller is to regulate a measure of fluid responsiveness to a desired value, the controller may achieve a measurement that is close to the desired value (with some error). Lower-level controller design parameters can be changed to adjust the value of this error.
  • the lower-level controller focused on cardiovascular drug administration uses an adaptive control framework to regulate a hemodynamic measure to a desired value by adjusting the cardiovascular drug infusion rate.
  • the lower-level controller can regulate mean arterial pressure, systolic pressure, diastolic pressure, heart rate, cardiac output, stroke volume, systemic vascular resistance, or cardiac index.
  • the administered cardiovascular drug is a vasopressor and the lower-level controller can regulate mean arterial pressure, systolic pressure, systemic vascular resistance, or diastolic pressure.
  • the administered cardiovascular drug is an inotropic agent and the lower-level controller can regulate cardiac output, cardiac index, mean arterial pressure, systemic vascular resistance, or heart rate.
  • the administered cardiovascular drug is a chronotropic agent
  • the lower-level controller can regulate heart rate or cardiac output. While the goal of this lower-level controller is to regulate a hemodynamic measure to a desired value, the controller may achieve a measurement that is close to the desired value (with some error). Lower-level controller design parameters can be changed to adjust the value of this error.
  • the role of the higher-level, logic-based controller is different depending on whether the system is used to fully automate or partially automate fluid resuscitation and/or cardiovascular drug administration.
  • the higher-level, logic-based controller monitors the performance of the lower-level adaptive controller(s) and the patient's response to therapy.
  • a measure of fluid responsiveness or tissue perfusion is monitored (e.g., mean arterial pressure, stroke volume variation, pulse pressure variation, systolic pressure variation, dynamic arterial elastance, pleth variability index etc.) and in case of cardiovascular drug administration, a measure of hemodynamic function is monitored (e.g., mean arterial pressure, heart rate etc.).
  • the higher-level controller can “disengage” the lower-level controller(s) (if the system is used for full automation of fluid resuscitation) or the higher-level controller will stop providing suggested infusion rates and will alert the end-user (if the system is used for partial automation of fluid resuscitation).
  • Time stamps, infusion rates and measurement data can be sent to an internal or external database by the higher-level controller for archiving purposes.
  • the higher-level controller can also determine the timing of engaging each lower-level controller. In some embodiments, the higher-level controller engages the fluid resuscitation module first, and if some performance criteria is not met after a period of time, the drug administration module is also engaged. The higher-level controller (in clinical decision support) can also determine the when to notify the user. In some embodiments, the higher-level controller notifies the user only if the difference between the newly computed infusion rate by the lower-level controller and the last user-approved infusion rate is higher than some threshold.
  • the higher-level controller in a partial automation application, can use end-user response (to accept or reject the suggested infusion rate) to update the internal state of the lower-level controller.
  • the higher-level controller in both full automation and partial automation, can change the internal states of the lower-level controller(s) if the computed infusion rate is out of a “safe” range defined by the end-user.
  • the higher-level controller if the infusion rate computed by the lower-level controller exceeds the maximum allowable infusion rate then the higher-level controller resets the internal parameters and variables of the controller to preset default values.
  • the higher-level controller can also provide recommendation to the user to engage the cardiovascular drug administration module if a patient's hemodynamic variable of interest is not improved after a certain period of time after fluid resuscitation.
  • the higher-level controller asks the user to engage the fluid resuscitation module first, and if some performance criteria is not met after a period of time, asks the user to engage the drug administration module.
  • the higher-level controller asks the user to engage the cardiovascular drug administration module first, and if some performance criteria is not met after a period of time, asks the user to engage the fluid resuscitation module.
  • FIG. 2A illustrates the overall architecture of a fully automated closed-loop fluid resuscitation system or a fully automated closed-loop cardiovascular drug administration system of the disclosure.
  • a sensor e.g., hemodynamic monitor
  • the higher-level controller monitors the performance of the lower-level controller and the response of the patient to fluids or cardiovascular drugs by monitoring measurements from the sensor, internal state of the lower-level controller, and infusion rate computed by the lower-level controller (which is sent to the infusion pump by the higher-level controller).
  • the lower-level controller can send or receive data from the higher-level logic controller.
  • the higher-level controller can send or receive data from the lower-level controller.
  • the human user can interact with the closed-loop system through a user interface to set a target value for the measurement (e.g., set target stroke volume variation of 13% or set mean arterial pressure of 65 mmHg), set the range of “safe” infusion rates (e.g., between 0 and 3,000 mL/hr for fluids or 0 and 0.5 mcg/kg/min for a vasopressor), start and stop the system, or set a backup infusion rate in case of loss of sensor signal (e.g., 1,000 mL/hr for fluid or 0.2 mcg/kg/min for vasopressor).
  • a target value for the measurement e.g., set target stroke volume variation of 13% or set mean arterial pressure of 65 mmHg
  • range of “safe” infusion rates e.g., between 0 and 3,000 mL/hr for fluids or 0 and 0.5 mcg
  • the lower-level controller processes a patient's data received from a sensor or a hemodynamic monitoring device (external or built-in), and sends computed infusion rates to the higher-level controller.
  • the higher-level controller ensures that the infusion rate meets all requirements (e.g., it is in the safe range) and if so sends a command to an infusion pump (external or built-in), which administers fluids or cardiovascular drugs to the patient.
  • FIG. 2B illustrates the overall architecture of a fully automated closed-loop fluid resuscitation system and cardiovascular drug administration system of the disclosure.
  • the closed-loop system provides both fluid and cardiovascular drug simultaneously.
  • One or two sensors e.g., hemodynamic monitor and vital sign monitor
  • the higher-level controller monitors the performance of the lower-level controllers and the response of the patient to fluid and cardiovascular drug by monitoring measurements from the sensors, internal state of the lower-level controllers, and infusion rates computed by the lower-level controllers (which are sent to two different infusion pumps by the higher-level controller: a fluid infusion pump and a cardiovascular drug infusion pump).
  • Lower-level controllers can send or receive data from the higher-level logic controller.
  • the higher-level controller can send or receive data from the lower-level controllers.
  • the human user can interact with the closed-loop system through a user interface to set a target value for the measurement or measurements (e.g., set target stroke volume variation of 13% and mean arterial pressure of 65 mmHg), set the range of “safe” infusion rates (e.g., between 0 and 3,000 mL/hr for fluids and 0 and 0.5 mcg/kg/min for a vasopressor), start and stop the system, or set a backup infusion rate in case of loss of sensor signal (e.g., 1,000 mL/hr for fluid and 0.2 mcg/kg/min for vasopressor).
  • a target value for the measurement or measurements e.g., set target stroke volume variation of 13% and mean arterial pressure of 65 mmHg
  • range of “safe” infusion rates e.g., between 0 and 3,000 mL/hr for fluids and 0 and 0.5
  • the lower-level controllers process patient's data received from one or more sensors or a hemodynamic monitoring devices (external or built-in), and sends computed infusion rates to the higher-level controller.
  • the higher-level controller ensures that the infusion rate meets all requirements (e.g., they are in the safe range) and if so sends a commands to infusion pumps (external or built-in), which administer fluids and cardiovascular drugs to the patient.
  • Data measured from sensors used by the lower-level fluid module and lower-level cardiovascular drug administration module may be the same (e.g., mean arterial pressure for both modules) or different (e.g., stroke volume variation for fluid module and mean arterial pressure for cardiovascular drug module).
  • FIG. 3A illustrates the overall architecture of a partially automated (clinical decision support) fluid resuscitation or cardiovascular drug administration system of the disclosure.
  • a monitoring device or sensor e.g., hemodynamic monitor, vital sign monitor, urometer, etc.
  • the higher-level controller monitors the performance of the lower-level controller and the response of the patient to fluids or cardiovascular drugs by monitoring measurements from the sensor, internal state of the lower-level controller, and infusion rate computed by the lower-level controller and the action taken by the human user (clinician).
  • the lower-level controller can send or receive data from the higher-level logic controller.
  • the higher-level controller can send or receive data from the lower-level controller.
  • the human user can interact with the partially automated (clinical decision support) system through a user interface to set a target value for the measurement (e.g., set target stroke volume variation of 13% or set target mean arterial pressure of 65 mmHg), set the range of “safe” infusion rates (e.g., between 0 and 3,000 mL/hr for fluid or 0 to 0.5 mcg/kg/min for vasopressor), and start and stop the system.
  • the lower-level controller can process a patient's data received from a sensor or a hemodynamic monitoring device (external or built-in), and send recommended infusion rates to the user interface to be displayed. The human user can then either accept or change the recommended rate to an acceptable value.
  • the human user can then manually change the infusion rate on the pump (if pump is not built-in or a pump that is not connected to the system by wire or wireless connection) or instruct the system to change the infusion rate (for built-in or a pump that is connected to the system by wire or wireless connection).
  • FIG. 3B illustrates the overall architecture of a partially automated (clinical decision support) fluid resuscitation and cardiovascular drug administration system of the disclosure.
  • a monitoring device or sensor or two monitoring devices and sensors e.g., hemodynamic monitor, vital sign monitor, urometer
  • the higher-level controller monitors the performance of the lower-level controllers and the response of the patient to fluids and cardiovascular drugs by monitoring measurements from the sensor or sensors, internal state of the lower-level controllers, and infusion rate computed by the lower-level controllers and the action taken by the human user (clinician).
  • Lower-level controllers can send or receive data from the higher-level logic controller.
  • the higher-level controller can send or receive data from the lower-level controllers.
  • the human user can interact with the partially automated (clinical decision support) system through a user interface to set a target value for the measurement or measurements (e.g., set target stroke volume variation of 13% and set target mean arterial pressure of 65 mmHg), set the range of “safe” infusion rates (e.g., between 0 and 3,000 mL/hr for fluid and 0 to 0.5 mcg/kg/min for vasopressor), and start and stop the system.
  • Lower-level controllers can process patient's data received from one or more sensors or hemodynamic monitoring devices (external or built-in), and send recommended infusion rates to the user interface to be displayed. The human user can then either accept or change the recommended rate to an acceptable value.
  • the human user can then manually change the infusion rate on the pump, if the pump is not built-in or a pump is not connected to the system by wire or wireless connection.
  • the human user can also manually instruct the system to change the infusion rate for a built-in pump or a pump that is connected to the system by wire or wireless connection.
  • FIG. 4A illustrates components of a fully automated, closed-loop fluid resuscitation or cardiovascular drug administration system of the disclosure.
  • a hemodynamic monitor or sensor sends a patient's data to a sensor measurement database.
  • An infusion rate computation engine which is embedded in the lower-level controller, retrieves sensor measurements and computes infusion rates. The infusion rates (and the corresponding sensor measurements) are communicated with an infusion rate database.
  • the infusion rate computation engine can send data to the infusion rate database and an infusion rate verification system.
  • the infusion rate verification system which is embedded in the higher-level logic-based controller, ensures the computed rates meet the requirements and if acceptable sends the newly computed infusion rate to the infusion pump controller.
  • the infusion pump controller then automatically changes the infusion rate of the infusion pump to administer an amount of fluid or cardiovascular drug based on commands received by the infusion pump controller.
  • FIG. 4B illustrates components of a fully automated, closed-loop fluid resuscitation and cardiovascular drug administration system of the disclosure.
  • the overall system is composed of two subsystems: a subsystem for fluid management and a subsystem for cardiovascular drug management.
  • a hemodynamic monitor or sensor sends a patient's data to a sensor measurement database.
  • An infusion rate computation engine which is embedded in the lower-level controller, retrieves sensor measurements and computes infusion rates. The infusion rates and the corresponding sensor measurements are communicated with an infusion rate database.
  • the infusion rate computation engine can send data to the infusion rate database and an infusion rate verification system.
  • the infusion rate verification system which is embedded in the higher-level logic-based controller, ensures the computed rates meet the requirements and if acceptable sends the newly computed infusion rate to the infusion pump controller.
  • the infusion pump controller then automatically changes the infusion rate of the infusion pump to administer an amount of fluid or cardiovascular drug based on commands received by the infusion pump controller.
  • FIG. 5A illustrates components of a partially-automated clinical decision support fluid resuscitation or cardiovascular drug administration system of the disclosure.
  • a hemodynamic monitor or sensor sends a patient's data to a sensor measurement database.
  • An infusion rate computation engine which is embedded in the lower-level controller, retrieves sensor measurements and computes infusion rates. The infusion rates and the corresponding sensor measurements are communicated with an infusion rate database.
  • the infusion rate computation engine sends data to the infusion rate verification system, which is embedded in the higher-level logic-based controller.
  • the infusion rate verification system ensures the computed rates meet the requirements including the requirement to notify the user of significant changes in infusion rate and if acceptable notifies the clinician using a user interface.
  • the recommended new infusion rate is presented to the clinician, who either approves the recommended infusion rate or requests a modification of the rate based on the clinician's qualitative judgement.
  • the approved or modified infusion rate is sent to a database archiving clinician approved infusion rates.
  • the clinician administers the approved or modified fluid or cardiovascular drug by either changing the infusion rate manually, if a pump is not built-in or the pump is not connected to the system by wire or wireless connection.
  • the clinician can also instruct the system to change the infusion rate to the approved value if a pump is built-in or a pump is connected to the system by wire or wireless connection.
  • FIG. 5B illustrates components of a partially-automated clinical decision support fluid resuscitation and cardiovascular drug administration system of the disclosure.
  • the overall system is composed of two subsystems: a subsystem for fluid management and a subsystem for cardiovascular drug management.
  • a hemodynamic monitor or sensor sends a patient's data to a sensor measurement database.
  • An infusion rate computation engine retrieves sensor measurements and computes infusion rates. The infusion rates and the corresponding sensor measurements are communicated with an infusion rate database.
  • the infusion rate computation engine which is embedded in the lower-level controller, can send data to the infusion rate verification system.
  • the infusion rate verification system which is embedded in the higher-level logic-based controller, ensures the computed rates meet the requirements including the requirement to notify the user of significant changes in infusion rate and if acceptable notifies the clinician using a user interface.
  • the recommended new infusion rates are presented to the clinician, who either approves the recommended infusion rates or requests a modification of the rates based on the clinician's qualitative judgement.
  • the approved or modified infusion rates are sent to a database archiving clinician approved infusion rates.
  • the clinician administers the approved or modified fluid and cardiovascular drug by changing the infusion rates manually if a pump is not built-in or a pump that is not connected to the system by wire or wireless connection.
  • the clinician can also administer the approved or modified fluid and cardiovascular drug by instructing the system to change the infusion rates to the approved value if a pump is built-in or a pump is connected to the system by wire or wireless connection.
  • Example 1 Computing Fluid or Drug Infusion Rates Using Lower-Level Adaptive Control Architecture
  • the present disclosure describes a process of computing the fluid or cardiovascular drug infusion rate using lower-level adaptive control architecture.
  • the lower-level adaptive control architecture is applied to a problem involving only fluid administration, only cardiovascular administration, or fluid and cardiovascular drug administration.
  • two lower-level adaptive controllers running in parallel are implemented to compute infusion rates for fluid and cardiovascular drug.
  • the fluid or cardiovascular drug infusion rate is computed using lower-level adaptive control architecture through the following steps:
  • FIG. 6 details a flow chart of the lower-level adaptive control architecture of the disclosure outlining steps 1)-9).
  • a two-compartment model is used to build the closed-loop fluid resuscitation architecture.
  • the same approach is applied for compartmental models with 3 or more compartments.
  • a blood (t) denotes the rate of loss of protein (albumin) mass from hemorrhage
  • Q t (t) is the rate of albumin mass transfer from circulation to interstitial tissue
  • Q L (t) is the rate of albumin mass transfer from interstitial tissue to circulation.
  • f 1 (v) and f 3 (v) denote functions characterizing the rate of change of fluid in circulation and tissue compartments, respectively
  • f 2 (v) and f 4 (v) denote functions characterizing the rate of change of albumin in circulation and tissue compartments, respectively
  • g(v(t)) characterizes the effect of fluid infusion on the compartmental model. Note that variables indicating exchange of volume or mass with the outside environment including, J urine (t), J blood (t), J evaporation (t), and a blood (t) have been incorporated into functions f 1 (v), f 2 (v), and f 3 (v).
  • the original two-compartment model is then modified to introduce a certain structure in the dynamics.
  • a fictitious state, x f (t) is added such that the fictitious state follows the same trend as the volume of fluid in circulation, v c (t), with some time lag.
  • error variables are defined that quantify the deviation of each variable from its equilibrium state (steady state value).
  • a series of basis functions are used, such as neural networks basis functions (e.g., radial basis functions or sigmoids), wavelets, or Fourier functions, to approximate h( ⁇ ) and ⁇ ( ⁇ ).
  • basis functions e.g., radial basis functions or sigmoids
  • wavelets e.g., wavelets
  • Fourier functions e.g., Fourier functions
  • h ( ⁇ ) w p T ( t ) p ( ⁇ )+ ⁇ p (17)
  • ⁇ ( ⁇ ) w q T ( t ) q ( ⁇ )+ ⁇ q (18)
  • s ⁇ ( ⁇ _ ) ⁇ ⁇ ⁇ 1 1 + e ⁇ ⁇ ( ⁇ _ - ⁇ _ 0 ) , ⁇ , t 0 ⁇ , can be used.
  • ⁇ 1 , ⁇ 2 , c 1 , and c 2 can be selected such that
  • a ⁇ ⁇ ⁇ [ c 2 c 1 ⁇ 1 ⁇ 2 ] , ( 19 ) is asymptotically stable (i.e., the real parts of all the eigenvalues of A are negative).
  • c 1 100
  • c 2 ⁇ 100
  • a two-compartment model is used to build the closed-loop cardiovascular administration architecture disclosed herein.
  • the same approach is applied for compartmental models with 3 or more compartments.
  • f 1 (d) and f 2 (d) denote functions characterizing the rate of change of drug mass in circulation and tissue compartments, respectively, g(d(t)) characterizes the effect of cardiovascular drug infusion on the compartmental model.
  • variables indicating exchange of mass with the outside environment that is, J other (t), and J M (t) have been incorporated into function f 1 (d), and f 2 (v).
  • the functions f 1 (d), f 2 (d), and g(d) are generally unknown for each individual patient.
  • the original two-compartment model is then modified to introduce a certain structure in the dynamics.
  • a fictitious state, x f (t) is added such that the fictitious state follows the same trend as the cardiovascular drug mass in circulation, d c (t), with some time lag.
  • error variables are defined that quantify the deviation of each variable from its equilibrium state (steady state value).
  • a series of basis functions are used, such as neural networks basis functions (e.g., radial basis functions or sigmoids), wavelets, or Fourier functions, to approximate h( ⁇ ) and ⁇ ( ⁇ ).
  • basis functions e.g., radial basis functions or sigmoids
  • wavelets e.g., wavelets
  • Fourier functions e.g., Fourier functions
  • s ⁇ ( ⁇ _ ) ⁇ ⁇ ⁇ 1 1 + e ⁇ ⁇ ( ⁇ _ - ⁇ _ 0 ) , ⁇ , t 0 ⁇ , can be used.
  • ⁇ 1 , ⁇ 2 , c 1 , and c 2 can be selected such that
  • a ⁇ ⁇ ⁇ [ c 1 c 2 ⁇ 1 ⁇ 2 ] , ( 32 ) is asymptotically stable (i.e., the real parts of all the eigenvalues of A are negative).
  • c 1 0.2
  • c 2 0.013
  • ⁇ 1 0
  • ⁇ 2 ⁇ 0.2.
  • the infusion rate of the controller (for fluid or cardiovascular drug) is given by
  • m(t) represents the smoothed (denoised) sensor measurement used as an endpoint for fluid or drug administration (e.g., stroke volume variation, urine output rate, mean arterial pressure, central venous pressure, systolic pressure variation, etc. for fluid resuscitation; and mean arterial pressure, heart rate, systolic pressure, diastolic pressure, systemic vascular resistance, central venous pressure, etc. for cardiovascular drug administration) at time t.
  • fluid or drug administration e.g., stroke volume variation, urine output rate, mean arterial pressure, central venous pressure, systolic pressure variation, etc. for fluid resuscitation; and mean arterial pressure, heart rate, systolic pressure, diastolic pressure, systemic vascular resistance, central venous pressure, etc. for cardiovascular drug administration
  • u(t) represents computed infusion rate at time t.
  • smoothed (denoised) sensor measurement can be obtained by a moving window average where the mean value of the sensor measurement in a time window (e.g., 2 minutes) is computed and assigned to m(t).
  • Sensor values can be preprocessed to drop measurements that appear to be noisy or invalid and only acceptable values are included in the window averaging.
  • ⁇ ⁇ ( ⁇ , y ) ⁇ ⁇ ⁇ ⁇ y , if ⁇ ⁇ f ⁇ ( ⁇ ) ⁇ 0 , y , if ⁇ ⁇ f ⁇ ( ⁇ ) ⁇ 0 , and ⁇ ⁇ ⁇ f T ⁇ y ⁇ 0 , y - ⁇ f ⁇ ⁇ f ⁇ ⁇ ⁇ ⁇ f ⁇ ⁇ f ⁇ , y ⁇ ⁇ f ⁇ ( ⁇ ) , if ⁇ ⁇ f ⁇ ( ⁇ ) ⁇ 0 ⁇ ⁇ and ⁇ ⁇ ⁇ f T ⁇ y > 0 , where f:R n ⁇ R is defined as
  • the patient model involved a compartmental model to model fluid distribution and the relationship between volume in circulation and SVV was based on a nonlinear relationship based on experimental results on dogs.
  • FIG. 7 shows stroke volume variation (SVV (%)) versus time.
  • the target stroke volume variation is 15%.
  • the SVV (%) starts at about 9%, and changes with the introduction of fluid resuscitation.
  • the SVV (%) increases to the target value of 15%.
  • the blood loss increases to 3 mL/kg/min, and the controller increases the infusion rate to drive stroke volume variation measurements to the target value of 15%.
  • FIG. 8 shows infusion rates computed by the adaptive control framework.
  • the infusion rate is rapidly increased to about 1500 mL/h to maintain an SVV (%) of 15%.
  • the blood loss increases to 3 mL/kg/min, and the controller increases the infusion rate to about 2250 mL/h to maintain the target SVV (%) of 15%.
  • FIG. 9 shows plasma volume in circulation versus time.
  • the plasma volume in circulation rapidly decreases due to loss of blood in spite of fluid resuscitation until reaching an equilibrium value of about 450 mL.
  • the blood loss increases to 3 mL/kg/min, and the controller increases the infusion rate to drive stroke volume variation measurements to the target value of 15%.
  • the plasma volume in circulation remains about the same even after an increase in blood loss.
  • the adaptive control framework of the disclosure was used to provide automated and semi-automated (clinical decision support) fluid resuscitation to five dogs in different hemorrhaging/hypovolemic scenarios.
  • Vascular catheters were surgically placed in the left jugular vein and right carotid and femoral arteries after perivascular administration of 0.5-1.0 ml 2% lidocaine.
  • the carotid or femoral artery catheter was connected to a HoTrac sensor with low-compliance fluid filled tubing.
  • the FloTrac sensor was connected to a Vigileo monitor for determination and continuous monitoring of SVV.
  • the FloTrac sensor was positioned and zeroed at the level of the sternum.
  • the pressure line of the FloTrac sensor was flushed with 4 ml/hr of lactated ringer's solution (LRS).
  • Heart rate was determined from a Lead II electrocardiogram (ECG). Criteria for obtaining accurate SVV recordings during mechanical ventilation were employed.
  • a 5 Fr Swan-Ganz catheter was percutaneously advanced via the right jugular vein (2 dogs) into the pulmonary artery under fluoroscopic guidance for measurement of cardiac output by thermodilution.
  • cardiac output was determined by a previously implanted flow probe (3 dogs) positioned around the ascending aorta, proximal to brachio-cephalic trunk for continuous recording of cardiac output.
  • Absolute uncontrolled hypovolemia (S3-1, S4-2, S5-2; 3 trials), designed to simulate blood loss from a severed artery was produced by withdrawal of approximately 50% (40 ml/kg) of the dogs estimated blood volume (80 ml/kg) from the right carotid or right femoral artery over one hour. Five successive 8.0 ml/kg increments of blood were withdrawn continuously in increments that were completed at approximately 7-8, 18-20, 30-32, 43-45, and 60 minutes after initiating hemorrhage. Closed-loop fluid resuscitation was initiated 10 minutes after initiation of absolute uncontrolled hypovolemia (i.e., beginning of Stage 2 of blood withdrawal) and continued until SVV reached a predetermined target range equal to or less than 13 ⁇ 3%.
  • Relative hypovolemia (2 trials) was produced by either increasing the inspired concentration of isoflurane to 2.0-2.5 MAC (S5-1, 1 trial) or administering sodium nitroprusside (5-10 mcg/kg/min; S4-1, 1 trial) until mean arterial blood pressure was ⁇ 50 mm Hg.
  • the target range SVV was set at 13 ⁇ 3% for S4-1 and 5 ⁇ 3% for S5-1.
  • Relative and controlled absolute hypovolemia were produced by increasing the concentration of isoflurane (0.25-0.5%, 1.5-2.0 MAC multiples) in order to decrease MAP by ⁇ 30% (S2-1, 1 trial) or administering sodium nitroprusside (1-15 mcg/kg/min; S2-2, 1 trial) followed by withdrawal of 15 ml/kg/minutes of blood.
  • the target range SVV was set at 13 ⁇ 3% for S2-1 and S2-2.
  • the subject was resuscitated to the target SVV value in S2-1 and stabilized before initiating the second study (S2-2). Fluid resuscitation started 15 minutes after achieving relative and controlled absolute hypovolemia.
  • the closed-loop fluid resuscitation system was employed in a “partial automation” mode (clinical decision support) in two experimental trials, one involving absolute uncontrolled hemorrhage (S4-2) and one involving relative hypovolemia from sodium nitroprusside administration (S4-1), where the system displayed the recommended infusion rate every minute and the user manually changed the infusion rate.
  • a Horizon N ⁇ T Modular Infusion System pump was used in the partial automated mode. While the system was able to provide infusion rate recommendations more frequently, an update interval of 1 minute was chosen to allow sufficient time for the clinical staff to adjust the pump settings manually.
  • Measured SVV values were filtered in all studies, including automated and partially automated modes, using a 1-minute moving window averaging to remove noise.
  • the adaptive controller was implemented using a neural network with sigmoidal basis functions to use as the function approximator.
  • the subject continuously received a fluid infusion and the control system changed the infusion rate every few seconds in response to changes in SVV.
  • Vigileo transmitted the most recent value of the SVV measurement every 2 seconds using serial communication.
  • the adaptive control framework was implemented on a laptop. The laptop was connected to the Vigileo using a Serial to USB cable.
  • the closed-loop fluid resuscitation system used a 1-minute moving window averaging to remove noise.
  • the control algorithm was implemented in the Python programming language running on a laptop with the Linux operating system. Measurements from Vigileo were recorded by the laptop using serial communication.
  • the closed-loop fluid resuscitation algorithm computed an infusion rate every 11 seconds using the average SVV values in the past 1-minute.
  • the infusion rate was sent by the laptop to an infusion pump (supporting flow rates from 0.06 to 4200 ml/hr) using a USB connection.
  • Performance Metrics Performance metrics that are of clinical relevance were defined in order to assess the performance of the closed-loop fluid resuscitation system. Specifically, T target was defined as the duration from start of fluid administration to restoration of an acceptable SVV target range.
  • the acceptable SVV target range was defined to be equal to 13 ⁇ 3% with the exception of two experiments, namely, S5-2 (uncontrolled hypovolemia) and S5-1 (relative hypovolemia), where the acceptable SVV target range was 10 ⁇ 3% and 5 ⁇ 3%, respectively.
  • the R in range was defined as the percentage of time that SVV stayed in the acceptable range once SVV target range was reached (i.e., duration of time SVV stayed in the acceptable range once SVV target range was reached divided by total duration of resuscitation).
  • Controlled Hypovolemia Absolute hypovolemia during 1.5 MAC isoflurane anesthesia decreased MAP from 100 to 86 mmHg (dog S ⁇ 1) and from 109 to 54 mm Hg (S1-2) after withdrawal of 15 ml/kg and then 40 ml/kg of blood respectively (Table 2).
  • Heart rate increased and cardiac output decreased after withdrawal of 15 ml/kg and 40 ml/kg of blood (Table 2).
  • the SVV increased after withdrawal of 15 ml/kg and 40 ml/kg of blood.
  • the SVV returned to the target range (13% ⁇ 3) after the administration of 7 ml/kg and 66 ml/kg of LRS, respectively (Table 2).
  • Uncontrolled Hypovolemia Closed-loop fluid administration was initiated during the second stage of blood withdrawal, and continued throughout hemorrhage (S3-1, S4-2, S5-2). Closed-loop fluid administration was stopped approximately 30 minutes after the end of the last (fifth) stage of hemorrhage as this exceeds the average time for fluid equilibration with the interstitial fluid compartment. Mean arterial blood pressure and cardiac output decreased and heart rate increased during the initial 3-4 stages of uncontrolled hypovolemia (Table 3). Heart rate increased throughout hemorrhage and remained elevated throughout hemorrhage and fluid administration (Table 3). The SVV increased during the first stage of uncontrolled hypovolemia and returned toward baseline values thereafter (Table 3).
  • the fluid administration system was used in a partially-automated (human-in-the-loop) mode for S4, where the recommended infusion rate was displayed to the user every minute and the user manually changed the infusion rate to the recommended value.
  • Relative Hypovolemia and Controlled Hypovolemia Increasing the isoflurane concentration from 1.5 to 2.5 MAC (S2-1) or administration of sodium nitroprusside (S2-2) was followed by blood withdrawal (15 ml/kg/15 minutes). The sodium nitroprusside infusion rate started at 1 mcg/kg/min and was increased to 15 mcg/kg/min. The target range SVV was set at 13 ⁇ 3%. Absolute hypovolemia (15 ml/kg/15 min) during 2.5 MAC isoflurane anesthesia decreased MAP from 60 mmHg before blood withdrawal to 39 mm Hg after blood withdrawal (S2-1). In addition, MAP increased from 39 mmHg to 46 mmHg after a 15-minute stabilization period.
  • Heart rate changed minimally (110 vs. 112 bpm) and cardiac output decreased 20% (1.0 vs. 0.8 L/min) after the production of relative hypovolemia combined with controlled hypovolemia (15 ml/kg/15 min).
  • the SVV increased from 13% at 1.5 MAC to 21% at 2.5 MAC and then to 41% after withdrawal of 15 ml/kg of blood.
  • the SVV decreased to 26% after a 15-minute stabilization period.
  • the SVV returned to the target range (13% ⁇ 3) at 43 minutes (T target ) after the administration of 78 ml/kg of LRS.
  • the maximum fluid administration rate (u max ) was 113 ml/kg/hr.
  • Heart rate decreased (112 to 99) and cardiac output increased to above the baseline value (1.0 vs. 1.2) after LRS administration but MAP remained relatively unchanged (43 mm Hg) until the isoflurane concentration was decreased.
  • the closed-loop fluid resuscitation system used the compartmental modeling framework to compute fluid infusion rates.
  • the two-compartment model of the microvascular exchange system involved parameters that are generally unknown and different from patient to patient. In addition, the two-compartment model was only an approximation of the fluid distribution in the body, resulting in modeling error.
  • the adaptive control fluid resuscitation algorithm uses the compartmental characteristics of the fluid distribution in the body.
  • the adaptive algorithm used a “function approximator.”
  • the function approximator was characterized by a set of parameters, which were continuously estimated by the closed-loop system in real-time.
  • the closed-loop fluid resuscitation system re-computes the fluid infusion rate periodically.
  • the function approximator used the values of infusion rates and SVV measurements to estimate the dynamics of fluid distribution.
  • the controller performance was evaluated with computer simulations on a two-compartment model prior to conducting the animal study. The results presented are the first attempt to use the disclosure in live subjects.
  • the adaptive control algorithm was based on physiology, and the parameters of the model were estimated in real-time.
  • the framework provided a mechanism to account for inter-patient and intra-patient variability in the fluid resuscitation process.
  • FIGS. 10 and 11 show the results for 2 canine subjects 51 and S2 (total of 4 studies) experiencing controlled hemorrhage.
  • FIG. 10 shows changes in filtered SVV (%) versus time
  • FIG. 11 shows changes in infusion rate (mL/hr) versus time.
  • the target SVV was 13%.
  • the infusion rate dropped from 750 mL/hr to about 400 mL/hr to maintain an SVV of 13%.
  • the infusion rate fluctuated between 300-400 mL/hr to maintain an SVV of 13%
  • the infusion rate started from about 800 mL/hr increased to about 1000 ml/hr and decreased to about 850 ml/hr.
  • the infusion rate started from about 800 mL/hr and in the end reached about 650 ml/hr.
  • the infusion rate started from about 750 mL/hr and in about 30 minutes reached about 500 ml/hr but increased to 750 ml/hr.
  • FIGS. 12 and 13 shows the results for 3 canine subjects S3, S4, and S5 experiencing uncontrolled hemorrhage.
  • FIG. 12 shows changes in filtered SVV (%) versus time
  • FIG. 13 shows changes in infusion rate versus time.
  • the target SVV was 13% in studies S3-1 and S4-2 and was 10% in study S5-2.
  • study S4-2 the partial automation (clinical decision support) was used where every 1 minute the clinician used fluid rates recommended by the system to manually change the infusion rate on the pump.
  • the fully automated closed-loop system was used.
  • the infusion rate started from about 600 mL/hr and increased to about 1200 mL/hr to drive SVV to 13% and then dropped to 750 mL/hr.
  • the infusion rate started from about 750 mL/hr increased to 999 mL/hr and then decreased to about 600 mL/hr to drive SVV to 13%.
  • the infusion rate started from about 500 mL/hr and fluctuated between 400-600 mL/hr to drive SVV to the target value of 10%.
  • FIGS. 14 and 15 shows the fluid resuscitation of 2 canine subjects S4 and S5 that were hypotensive as a result of administration of sodium nitroprusside (in S4-1) and increase in the inhalant anesthetic isoflurane (in S5-1).
  • study S5-1 the fully automated closed-loop system was used while in study S4-1 the partially automated (clinical decision support) system was used where the recommended infusion rate was displayed every 1 minute to the user and the user changed the infusion rate on the pump manually.
  • FIG. 14 shows changes in filtered SVV (%) versus time
  • FIG. 15 shows changes in infusion rate versus time. The target SVV was 13% in S4-1 and 5% in S5-1.
  • the infusion rate was started at about 650 mL/hr and decreased to between 150-350 mL/hr once the target 13% was reached.
  • the infusion rate started at about 700 mL/hr and was kept close to this value until 25 minutes into the study, when the study was terminated as SVV approached the desired SVV of 5%.
  • the higher-level controller was designed as a rule-based expert system and served to:
  • a set threshold e.g. 2000 mL or 10,000 mcg
  • Performance degradation was defined as: i) a rapid change in weights (or coefficients) of the function approximator, that is,
  • threshold e.g., 0.1, or 1, 10 etc.
  • threshold value e.g., 1, 2, 3, 4, etc.
  • the higher-level controller disabled the lower-level controller and set the infusion rate to a backup the infusion rate set by the user.
  • fluid resuscitation Deciding when to Engage Fluid Resuscitation and Cardiovascular Drug Administration Modules.
  • fluid resuscitation it is preferable to provide fluid resuscitation first, and if unsuccessful in achieving an acceptable condition, administer a cardiovascular drug such as a vasopressor.
  • the higher-level controller first engaged the fluid resuscitation module and monitored the patient. After a period of time when a clinically relevant hemodynamic variable (e.g., mean arterial pressure) was not improved in spite of fluid resuscitation (e.g., the mean arterial pressure was not in the acceptable range of 65-80 mmHg after 30 minutes), the higher-level controller engaged the cardiovascular drug administration module to administer a vasopressor.
  • a clinically relevant hemodynamic variable e.g., mean arterial pressure
  • the clinician instructed the higher-level controller to engage the cardiovascular drug administration module while the fluid resuscitation module was already running. In some embodiments, the clinician instructed the higher-level controller to engage the fluid resuscitation module while the cardiovascular drug administration module was already running. In this scenario, stroke volume variation was not improved by only administering a cardiovascular drug (e.g., a vasopressor) and the higher-level controller engaged the fluid resuscitation module.
  • a cardiovascular drug e.g., a vasopressor
  • FIG. 16 illustrates the components of the higher-level controller for the closed-loop fluid resuscitation and/or cardiovascular drug administration system.
  • the higher-level controller can monitor the fluid resuscitation module and/or the cardiovascular drug administration depending on whether the system is used for fluid resuscitation only, for cardiovascular drug administration only, or combined fluid resuscitation and cardiovascular drug administration.
  • the lower-level controller (fluid resuscitation module or cardiovascular drug administration module or both) sent newly computed infusion rate to the higher-level controller.
  • the lower-level controller sent newly computed infusion rate to the higher-level controller.
  • the higher-level controller compared the new rate with the last user approved rate (i.e., for a fluid resuscitation, the newly computed fluid infusion rate was compared with the last user-approved fluid infusion rate, and for cardiovascular drug administration, drug infusion rate was compared with the last user-approved drug infusion rate).
  • the threshold value e.g. 25% of the last approved rate
  • the infusion rate was not changed, the user was not notified, and the lower-level controller continued its operation. If the difference between the new infusion rate and the last user-approved rate was higher than some threshold (e.g., 25% of the last approved rate), then the recommended infusion rate was displayed to the user through the graphical user interface. If the user accepted the infusion rate, the higher-level controller allowed the lower-level controller to continue its operation and the infusion rate was updated to the new rate.
  • the higher-level controller reset the controller and set the weights of the function approximator such that the infusion rate computed by the lower-level controller matched the infusion rate entered by the user.
  • the infusion rate was also updated to the rate provided by the user.
  • FIG. 17 illustrates the components of the higher-level controller for the clinical decision support case.
  • FIG. 18 shows mean arterial pressure (MAP) versus time.
  • the target MAP was 75 mmHg, and the 65-75 mmHg region is highlighted on the graph.
  • MAP started at below 60 mmHg, and changes with the introduction of vasopressor epinephrine.
  • the MAP increased to the target value of 75 mmHg.
  • FIG. 19 shows infusion rates computed by the adaptive control framework.
  • the infusion rate gradually increased and then started to decrease as MAP started to approach the target MAP of 75 mmHg reaching a low infusion rate of 0.85 mcg/kg/min.
  • the infusion rate then started to gradually increase to maintain MAP of 75 mmHg.
  • Example 8 Computer Simulations for Fluid Administration Using Mean Arterial Pressure
  • the patient model involved cardiovascular modeling to model hemodynamics and a compartmental model to model fluid distribution.
  • FIG. 20 shows mean arterial pressure (MAP) versus time.
  • the target MAP is 75 mmHg and the 65-75 mmHg region is highlighted on the graph.
  • MAP starts at approximately 45 mmHg, and changes with the introduction of crystalloid fluid.
  • the MAP increases to the target value of 75 mmHg.
  • FIG. 21 shows infusion rates computed by the adaptive control framework.
  • the initial infusion rate was chosen was approximately 140 mL/min.
  • the infusion rate gradually increased to 160 mL/min and then decreased to around 80 ml/min.
  • Adaptive control frameworks were used to simulate fluid resuscitation and cardiovascular drug (vasopressor epinephrine) administration for a 70 kg patient with hypotension as a result of sepsis.
  • the goal was to maintain the mean arterial pressure at 75 mmHg and stroke volume variation (SVV) of 12%.
  • the simulation involved crystalloid fluid and epinephrine (vasopressor).
  • the fluid resuscitation module used SVV data to compute fluid infusion rates
  • the cardiovascular drug administration module used mean arterial pressure (MAP) to compute the vasopressor infusion rates.
  • the higher-level controller first engaged the fluid resuscitation module to provide fluid infusion. After 30 minutes, the higher-level controller engaged the cardiovascular drug administration module as mean arterial pressure was not improved after fluid infusion.
  • the patient model involved cardiovascular modeling to model hemodynamics and compartmental model to model fluid distribution. The start of simulation is when the patient condition rapidly deteriorates.
  • FIG. 22 shows stroke volume variation (SVV (%)) versus time.
  • the target stroke volume variation was 12%.
  • the SVV (%) started at about 18%, and was reduced to 10% after fluid resuscitation.
  • SVV momentarily increased due to the administration of epinephrine (a transient vasodilatory effect).
  • SVV was approximately 11% and remained close to the target SVV value of 12%.
  • FIG. 23 shows fluid infusion rates computed by the fluid resuscitation adaptive control framework.
  • the infusion rate started at approximately 130 mL/min and was reduced to 40 mL/min after SVV was at an acceptable range.
  • FIG. 24 shows mean arterial pressure (MAP) versus time.
  • the target MAP was 75 mmHg and the 65-75 mmHg region is highlighted on the graph.
  • MAP dropped to 50 mmHg as the patient condition deteriorated.
  • MAP started to increase and approached the set value of 75 mmHg.
  • MAP was approximately 70 mmHg and remained close to the target MAP value of 75 mmHg.
  • FIG. 25 shows vasopressor infusion rates computed by the cardiovascular administration adaptive control framework.
  • the initial infusion rate was chosen to be approximately 0.12 mcg/kg/min. After a slight increase, the rate decreased to approximately 0.9 mcg/kg/min and then stabilized around 0.12 mcg/kg/min as MAP is maintained close to 70 mmHg.
  • a hardware platform was developed to implement the fluid resuscitation system and the cardiovascular drug administration system.
  • the system is composed of a processing module and an associated touchscreen.
  • the processing module is able to receive data from a hemodynamic monitor (invasive or non-invasive measurement) or a blood pressure module (either invasive measurement through a pressure transducer connected to an arterial line or non-invasive measurement) through a wired connection.
  • the processing module is able to send real-time infusion rate data through a wired connection to an infusion pump.
  • the touchscreen is used for displaying graphs such as received measurements over time and infusion rate over time.
  • the main dashboard also displays current measurement, current infusion rate, and total volume of fluid/drug infused.
  • the touchscreen allows the user to specify different parameters required by the system.
  • the user sets the target measurement value, initial infusion rate, backup infusion rate (in case of missing sensor data, the closed-loop system is disengaged and transitions to backup infusion rate until the user takes over) maximum infusion rate and other variables.
  • the touchscreen is used to communicate the new infusion rate value to request user's approval or give the user the ability to modify the rate.
  • the processing module updates the infusion rate of the infusion pump to the infusion rate approved by the user.
  • FIG. 26 is a system diagram of an embodiment of the hardware platform.
  • FIG. 27 is a block diagram illustrating an embodiment of the apparatus for displaying infusion therapy information for optimizing infusion therapy.
  • FIG. 28 depicts an embodiment of the apparatus for displaying infusion therapy information for optimizing infusion therapy.
  • the apparatus comprises a memory, a display, and one or more processor in operable communication with the memory and the display.
  • the processor is capable of receiving sensor-obtained hemodynamic measurements of a subject from a hemodynamic monitoring device.
  • the processor is further capable of issuing a prompt to the display upon determining an appropriate notification message and an appropriate change in infusion rate recommendation message, which are implicated upon detection of a change in infusion therapy.
  • the detection of a change in infusion therapy is based at least on hemodynamic measurements of a subject, an active infusion rate stored in the memory, and a background infusion rate computed by a lower-level controller.
  • an active infusion rate is a last user-approved infusion rate.
  • the last-approved infusion rate can be a last infusion rate that was recommended through a prompt and accepted by a user.
  • an active infusion rate can be an infusion rate obtained from an infusion pump that is actively administering fluid into a subject.
  • a background infusion rate is an infusion rate that upon updates to its value does not actively change the infusion rate of fluid or drug administered to a subject, but rather it updates in the background.
  • a background infusion rate is computed by a lower-level controller. In other embodiments, the background infusion rate can take on the value of an active infusion rate.
  • This may be through mechanisms such as a rejection of a recommended infusion rate prompted to a user which permits the user to manually override the recommendation with a desired infusion rate.
  • the desired infusion rate would become an active infusion rate and the background infusion rate, at least momentarily, would take on the value of this set desired infusion rate.
  • An appropriate notification message can alert a user that a new recommended infusion rate is available.
  • the notification message can alert a user that subject being treated with the infusion therapy is not improving based upon hemodynamic measurements.
  • the notification message can alert a user of a failure in receiving hemodynamic measurements from a monitoring device.
  • this notification message can alert a user of a failure in administering fluid, for instance, due to a status message received from an infusion pump.
  • the notification message can alert the user that received hemodynamic measurements exceed, equal, or drop below some threshold.
  • An appropriate change in infusion rate recommendation message can be a recommendation to increase or decrease the current active infusion rate.
  • an appropriate change in infusion rate recommendation message can be a specific value for infusion rate (e.g. 700 mL/hr, 300 mL/hr, 0 mL/hr). In one embodiment, this specific value can be 0 mL/hr, that is, to stop infusion of fluids or drugs to a patient, if an associated notification message alerts the user that the hemodynamic condition of a subject is not improving; in another embodiment, the recommendation to stop infusion of fluids or drugs may be due to an associated notification message that alerts the user that some hemodynamic measurement exceeds or drops below some threshold.
  • the notification message is generated only if the absolute difference between the active infusion rate and the background infusion rate is larger than a pre-determined threshold. In case the absolute difference between the active infusion rate and the background infusion rate is less than the pre-determined threshold then the value of the background infusion rate is ignored and the lower-level controller continues with computing new background infusion rates until the criterion for notifying the user is met.
  • the pre-determined threshold is a percentage of the active infusion rate (e.g, 1%, 2%, 5%, 10%).
  • the pre-determined threshold is an absolute value (e.g., 0.001 ml/hr, 0.1 ml/hr, 1 ml/hr, 10 ml/hr, 100 ml/hr, 1000 ml/hr).
  • the display can be a touchscreen-based display in which a user can interact with any prompt through touch gestures.
  • the display can be a non-touchscreen display and the user can interact with any prompt with suitable input devices, such as physical buttons, a mouse/trackpad, a keypad/keyboard, etc.
  • a detection of a change in infusion therapy can be performed by the higher-level logic-based controller based upon the performance criteria discussed earlier.
  • the detection of a change in infusion therapy occurs when an active infusion rate and a background infusion rate differ in value by some percentage (e.g. 5%, 10%, 12%, etc.) of the active infusion rate, some percentage of the background infusion rate, or some percentage of the average of the active and background infusion rate; in other embodiments, the difference can be some absolute value (e.g. ⁇ 50 mL/hr, 50 mL/hr, 100 mL/hr, etc.) which would trigger the detection.
  • a prompt 2810 that contains a slide to accept element or tap to reject element to the display containing a notification message 2820 and a change in infusion rate recommendation message 2830 .
  • an infusion rate can be set with infusion meter slider 2840 .
  • the active infusion rate remains unchanged and the background infusion rate is set to the same value as the unchanged active infusion rate.
  • the higher-level logic controller resets at least one element of the set of weights of the lower-level controller to a new value based at least in part on the background infusion rate.
  • the presented disclosure can be implemented in a way to minimize unnecessary interactions with the user regarding changes in infusion rates, which the user may deem acceptable or negligible.
  • the advantage of this implementation is that the clinical decision support system has a specific level of autonomy to automatically change infusion rates as long as the infusion rates are within the pre-approved range specified by the user.
  • the clinical decision support system can be coupled to an internal or external infusion pump.
  • the user can enter pre-approved ranges of infusion rates into the system with the intent that the system is authorized to change infusion rates automatically without requesting the user to approve the changes as long as the infusion rates fall within the pre-approved ranges.
  • the system automatically changes the infusion rate by instructing the pump and updating infusion rate on the graphical user interface as long as the new infusion rates are within the pre-approved infusion rates.
  • a pre-approved range can be entered using a lower limit and an upper limit (e.g., 50-100, 100-500, 500-1000 ml/hr).
  • the approved range can be entered based on the last user-approved infusion rate.
  • the user authorizes the clinical decision support system to internally approve infusion rates that are within a set distance (specified by the user) from the last user-approved infusion rate.
  • the user may authorize a pre-approved range of 500 ml/hr, in which case if the last user-approved infusion rate is 750 ml/hr the system is authorized to change the infusion rate as long as the new infusion rates are within 250 ml/hr to 1,250 ml/hr.
  • the user can specify a percentage change as a pre-approved range. For example, the user can approve a 10% change as a pre-approved range.
  • the clinical decision support system can internally approve new infusion rates in the range 900 ml/hr to 1,100 ml/hr without requesting user's approval.
  • the higher-level logic-based controller will compare the new infusion rate received from the lower-level controller with the pre-approved ranges. If the new infusion rate is within the pre-approved range (that is the new infusion rate is greater than or equal to the lower limit and less than or equal to the upper limit), then the higher-level logic can instruct the infusion pump to update the infusion rate to the new infusion rate value. However, if the new infusion rate falls outside the pre-approved range, the user is notified using the graphical user interface, where the user would approve, reject, or modify the new infusion rate.
  • the process starts by the user entering the pre-approved infusion rates into the system using the user interface.
  • the lower-level controller computes new infusion rates based at least in part on hemodynamic measurements.
  • the higher-level logic-based controller receives the newly computed infusion rates from the lower-level controller and determines whether the new infusion rate is within the pre-approved range. If so, it instructs the pump to update the infusion rate. Otherwise, it asks the user to approve, reject, or modify the new infusion rate.
  • the hierarchical control system described in this disclosure can be used for monitoring therapy to a subject in order to flag cases where the subject would receive lower or higher than expected infusion of a fluid or cardiovascular drug.
  • Both fluid and cardiovascular drug over-administration or under-administration is detrimental to the patient, and hence, a system that continuously monitors therapy including the infusion rate and patient's hemodynamic measurements and alerts the user if the patient is receiving more than expected or less than expected fluid and/or cardiovascular drug is desirable.
  • the system continuously monitors the patient's hemodynamic measurements, the type of therapy or therapies, and the infusion rate or infusion rates of the therapy or therapies, and notifies the user through a user interface if the patient is getting more than expected or less than expected fluid and/or cardiovascular drug.
  • this is implemented in a hemodynamic patient monitor at the bedside receiving information from the pump. In some embodiments, this is implemented as a software application as part of a remote patient monitoring platform, where information from hemodynamic monitors and infusion pumps are continuously analyzed and cases of over-administration or under-administration of fluid and/or cardiovascular drug is detected. In some embodiments, data from multiple hemodynamic monitors and infusion pump for different patients are all sent to the same remote location for analysis. In some embodiments, the system is implemented inside an infusion pump. In this case, the infusion pump receives hemodynamic measurement data from a hemodynamic monitor or other source.
  • the lower-level controller runs in the background and computes new infusion rates periodically.
  • the newly computed infusion rates are kept in the background, and analyzed by the higher-level logic-based controller.
  • the internal states of the lower-level controller are initialized such that the starting infusion rate generated by the lower-level controller matches the actual infusion rate specified by the user.
  • the lower-level controller uses a function approximator with a set of weights, where the weights are determined in a way such that the initial infusion rate generated by the lower-level controller matches the actual infusion rate specified by the user.
  • the function approximator is a neural network.
  • the lower-level controller periodically computes a new infusion rate in the background and sends the background infusion rate to the higher-level logic-based controller.
  • the higher-level controller records the current value of the background infusion rate and the current value of the actual infusion rate in a monitoring data base.
  • a monitoring module periodically analyzes the background infusion rate and the actual infusion rate. If the difference between the background infusion rate and the actual infusion rate is more than a set threshold (e.g., the difference between the rates are 1%, 5%, 10% etc. more or less than the actual infusion rate), then the monitoring module sends a command to the higher-level logic controller to notify the user of over-administration or under-administration.
  • the notification could be in the form of an audio/visual alarm or by generating a number or index indicating the difference between the actual infusion rate and the background infusion rate.
  • the monitoring module sends a command to the higher-level logic-based controller to notify the user when it identifies at least one entry in the monitoring database with an absolute value of difference between actual infusion rate and background infusion rate greater than a set threshold. In some embodiments, the monitoring module sends a command to the higher-level logic-based controller to notify the user when it identifies in the monitoring database at least two consecutive entries or two non-consecutive entries in a set time interval with an absolute value of difference between actual infusion rate and background infusion rate greater than a set threshold.
  • alarm system is implemented on an infusion pump, where the infusion pump periodically receives data from a hemodynamic monitor.
  • the audio and/or visual alarm can be generated on the infusion pump using a graphical user interface.
  • a dedicated light of a specific color e.g., red, or yellow, or blinking red, blinking yellow

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US11707571B2 (en) 2017-05-12 2023-07-25 Autonomous Healthcare, Inc. Hierarchical adaptive closed-loop fluid resuscitation and cardiovascular drug administration system

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